During physical activity, the energy demand of the human body greatly increases. Sustained exercise such as marathon running increases the whole-body energy requirement by 20-30 times over resting levels. The energy utilized to accommodate this demand, along with all other energy-requiring systems in the human body, comes in large part from the energy contained within ATP, adenosine triphosphate.
The most efficient, albeit slower, method of generating this ATP is under aerobic conditions, where oxygen is present and consumed. This method is named oxidation, or, the oxidative pathway. Different forms of fuel (e.g. proteins, fat, and carbohydrate) can be metabolized by oxidation to create ATP. The creation of ATP by aerobic means is typically favored by physical performance efforts of longer duration. The complete oxidation of one molecule of glucose yields up to 36 ATP molecules for skeletal muscle (38 for cardiac muscle).
As the intensity of effort increases, ATP is generated increasingly via another faster, but less efficient, pathway, anaerobic glycolysis, where glucose is metabolized to generate ATP (glycolysis) in the absence of oxygen (anaerobic). ATP is generated in the absence of oxygen only via anaerobic glycolysis. Being less efficient than oxidation, one molecule of glucose yields only 2 ATP molecules, far from the 36 obtained through oxidation. In addition, anaerobic glycolysis creates 2 lactic acid molecules for each glucose molecule metabolized. Increased use of the glycolytic system results in higher rates of glucose utilization, glycogen depletion, and lactic acid production.
The state of lactic acid is such that it dissociates almost totally into its ionized form resulting in lactate and a proton, or H+ (hydrogen ion), as follows:
TABLE 1Lactate-H (lactic acid)   Lactate− + H+Lactate itself may be metabolized by oxidation or converted to glucose or amino acids. In this way lactate may serve as a fuel substrate for work done by cardiac and skeletal muscle.
At lower levels of intensity and anaerobic glycolysis, the generation of every lactate molecule is matched by its removal/metabolism, and lactate does not tend to accumulate. Lactate will begin to accumulate, though, in untrained individuals when exercise reaches approximately 55 to 65% of their maximal capacity. Trained athletes, due to a combination of factors, are able to exercise at a higher intensity prior to the onset of lactate accumulation, at approximately 65 to 75% of maximal capacity. The intensity of effort at which this occurs for any given individual is designated that individual's blood lactate threshold. Beyond this limit, lactate begins to accumulate in the cellular environment followed by the measurable accumulation in the blood. The lactate threshold defines the onset of lactic acidosis, and also the onset of significant anaerobic glycolysis. The lactate threshold has been commonly defined as the highest oxygen consumption or exercise intensity resulting in at least a 1.0 millimolar (mM) increase in blood lactate level above the pre-exercise level.
As lactic acid levels rise the equation in Table 1 is directed to the right resulting in the generation of more H+, or hydrogen ions. The concentration (expressed by use of the common notation: [ ]) of hydrogen ions in the blood, [H+], determines whether the blood is acidic (pH<7.35), alkaline (pH>7.45), or normal (pH 7.35-7.45). Therefore, as lactic acid levels increase, [H+] increases, acidity increases, and pH is lowered. Lactic acidosis is a specific and very common pathologic acid/base disorder under the more general grouping of “metabolic acidosis” disorders. During intense physical exertion the accumulation of lactic acid, i.e., lactic acidosis, is the major contributor to the development of a metabolic acidosis. With regards to exercise and performance, it is not lactate that impairs performance, but rather the acidosis, or H+, component.
The bicarbonate ion (HCO3−) which is present in the blood is consumed as it buffers the lactic acid, or more specifically, the H+, created during exercise producing lactate, water and carbon dioxide as in the reaction of Table 2:
TABLE 2Lactate-H + HCO3   Lactate + H2CO3   H2O + CO2 + lactate−
As a result, blood bicarbonate levels drop in the presence of lactic (or metabolic) acidosis. This neutralization process and state of equilibrium can be simplified as seen in Table 3:
TABLE 3H+(as in lactic acid) + HCO3−   H2O + CO2 (aqueous)  CO2(gas phase)   ventilated
As the bicarbonate buffers the lactic acid, CO2 is generated in the aqueous phase. Aqueous CO2 dissolves across the pulmonary alveolar capillary membrane into the alveoli, which is then expired out through the lungs. The process whereby CO2 is expired and eliminated from the body is termed ventilation. The diffusion and elimination of CO2 across the pulmonary capillary membrane into the alveolus is very fast—at a rate approximately 20 times that of oxygen, due to the significantly greater solubility of CO2.
Table 3, when directed to the right, illustrates how blood acidity, or [H+], can be directly reduced by expiring, or ventilating, more CO2. It is the most efficient method of reducing hydrogen ions in the body. Increasing ventilation will result in a decrease in acidosis, or alternatively, an increase in alkalosis.
Using the current art, during exercise, absent the appearance of lactic acid, ventilation would otherwise increase in a linear manner with increasing exercise in order to provide normal oxidative cellular respiration, i.e., to supply needed oxygen and to clear metabolic waste products, including CO2. The excess CO2 created as a result of the buffering of lactic acid by bicarbonate is referred to as “non-metabolic CO2.” This non-metabolic CO2 represents an additional CO2 load imposed on the body beyond that of normal cellular respiration. Rising CO2 levels and acidosis are both potent stimulants of the brain's respiratory center and the human body responds with an autonomic, or involuntary action—increasing ventilation. In response to the appearance of lactic acid and new, non-metabolic, CO2 there is an involuntary, abrupt and measurable increase in ventilation over that which would be expected to satisfy normal cellular respiration.
This increase in ventilation is termed compensatory, as it represents a reflex physiologic adaptive response to an acute acid/base disorder, specifically, lactic acidosis. Its purpose is to maintain CO2 and thus, pH values, at a constant and normal level. The term ventilatory threshold (VT) is used to describe the point at which pulmonary ventilation begins to disproportionately increase in order to maintain normal CO2, and thus, pH, levels. The ventilatory threshold can be illustrated as seen in FIG. 1.
Ventilation may also be compared with corresponding blood levels of arterial CO2 and pH, as seen in FIG. 2. As a result of the compensatory increase in ventilation, pH, and alveolar, or arterial CO2 levels remain within normal limits.
Indeed, multiple acid/base disorders commonly co-exist. Most commonly, there is a single acid/base disturbance followed by a compensatory response. The final acid/base status reflects where the net balance of the equation seen in Table 3 lies. If there is an increase in the [H+], as would occur with lactic acidosis, the equation is directed to the left. Compensation for any acid/base disturbance is achieved by directing the equation in the opposite direction. In the case where [H+] increases, compensation would be to increase CO2 output. In this fashion, if more CO2 were eliminated than H+ generated, the net effect would be a net decrease in the [H+], i.e., a decrease in acidosis, or, increase in alkalosis. If this were achieved by respiratory means, e.g., by voluntarily and intentionally increasing ventilation, the process would be summarized as a metabolic acidosis with a compensatory respiratory alkalosis.
Thus, in exercise, the ventilatory threshold represents, in general, the onset of: 1) significant anaerobic glycolysis, 2) decreasing bicarbonate levels, 3) lactate accumulation, 4) metabolic, or, lactic acidosis, and 5) a compensatory respiratory alkalosis. As at all times during exercise or performance, the final pH of the blood will depend on where the balance of Table 3 will lie, that is, where the final balance between H+ accumulation and CO2 ventilation/elimination lies. Using the current art, pH and CO2 levels remain unchanged as the ventilatory threshold is passed.
In exercise using the current art, as the intensity of effort increases beyond the ventilatory threshold, the generation of lactic acid escalates. The generation of H+ eventually overwhelms the ventilation of CO2 and there is an overall net increase in the [H+], i.e., Table 3 is directed to the left. While up until this point blood pH has been normal, when the balance tips to the extent such that the net increase in [H+] equates to a blood pH of 7.35, the blood finally becomes, by definition, measurably acidic. In the current art, the point where this measurable acidosis (pH<7.35) starts is termed the Point of Metabolic Acidosis (PMA). Synonymous terms for this transition point are the Respiratory Compensation Threshold (RCT) or the Onset of Blood Lactate Accumulation (OBLA); however, PMA shall be preferentially used throughout this specification. With the onset of systemic acidosis, there is a cascade whereby any further increase in effort is met with exponentially decreasing efficiency. With increasing effort, lactic acid, and H+, accumulate in an accelerating fashion and the blood becomes increasingly more acidic. Concomitant with the PMA is another disproportionate compensatory increase in ventilation—with arterial CO2 values becoming similar to those values seen in hyperventilation.
At the PMA, increasing ventilation is done in an effort to drive the balance seen in Table 3 to the right in the face of a measurable acidosis. This is ineffectual and the [H+] continues to increase. The net direction of the balance seen in Table 3, despite maximum efforts in ventilation and trying to direct the balance seen in Table 3 to the right, is to the left. As the equation drives to the left, more CO2 is consumed in order to generate HCO3− to buffer the H+ and the end result is a net loss of CO2. A summary of these changes can be illustrated as seen in FIG. 3.
To understand the instant invention, though, one must look closer, specifically, to the area around the ventilatory threshold and the PMA. While blood pH and arterial CO2 measurements may be stated to be normal up until the PMA, there will still be measurable changes both in pH and partial pressure of CO2 (pCO2) despite levels remaining in established normal limits. Firstly, as it is known that ventilation was stimulated by a change in pCO2 and/or pH, there must have been a change to begin with. Secondly, there must be some travel from a normal resting average for blood pH, e.g. a pH of 7.4, down to the lower limits of normal, in the case of blood pH, 7.35. Both of these factors lead to the conclusion that there is a relative increase in acidosis, or decrease in alkalosis, even prior to the onset of a measurable abnormality. Indeed, it should be interpreted that there is a net shift in Table 3 to the left and the net accumulation of H+, i.e., an increase in acidosis or a decrease in alkalosis, following the ventilatory, or, lactate, threshold. Magnified, pH and pCO2 values between the ventilatory threshold and the PMA of FIG. 3 would appear as seen in FIG. 4. It is important to note that measurable changes in pH can occur as a result of very small changes in pCO2 levels.
The PMA is generally regarded as occurring around a lactate concentration of 4 mmol/L. Following this, there is a sharply decreasing ability to generate an increase in performance. Although there is considerable variability among individuals, the intensity of effort around the PMA is also thought to approximate the maximum exercise intensity that a person can sustain for a prolonged duration (in general, though, higher lactate levels, in the range of 7 or 8 mmol/L, can be tolerated for varying periods of time). For elite athletes, this lies around 75-90% of their maximum heart rate or oxygen consumption, and less than these values for more novice athletes and untrained individuals. Using the current art of exercise training, the popular term given to this approximate level, i.e., PMA, although possibly a misnomer, is that athlete's lactate, or anaerobic, threshold. This author intentionally excludes any reference to the PMA as being approximate to an individual's lactate or anaerobic threshold. Lactate threshold will continue to be defined as that level of oxygen consumption, heart rate, exercise intensity etc. at which there is a measurable increase in systemic lactic acid levels e.g. at least a 1.0 millimolar (mM) increase in blood lactate level above the pre-exercise level
Acidosis is one of, if not the most important determinants of maximal performance during intense athletic exercise. Acidosis is well known to adversely affect immediate muscle performance. Any systemic acidosis created by inefficient ventilation negatively affects cellular metabolism and the contractile capacity of active muscles. Deleterious effects of acidosis can be cumulative and chronic, lasting days, weeks, months etc.
In addition to the direct effects of acidosis on physiological performance, indirect effects also occur. For example, diaphragmatic function is impaired during acidosis, but not during alkalosis, leading to less efficient respiration and ventilation. Acidosis can lead to higher intra-muscular compartment pressures. This may be accompanied by muscle soreness, with indices of muscle damage, such as elevated CPK, LDH, and myoglobin, becoming measurable. The mechanism of this acute and chronic muscle damage phenomenon may be multi-factorial, but acidosis is likely a significant contributor.
Acidosis also leads to impaired hemodynamics. Indeed, macroscopic increases in muscle size following exercise are measurable by ultrasound. As muscle groups are typically bounded in closed compartments, an increase in compartmental volume leads to an increase in compartment pressure. Elevated compartment pressures will negatively affect the smallest and weakest vascular beds such as the smaller end-branch arterioles, arterio-venous capillaries, and venules, i.e., those vascular beds already carrying the least amount of oxygen. All of these mechanisms perpetuate and exacerbate oxygen delivery, CO2 clearance, and subsequently, acidosis.
Ventilation is an essential, but underutilized component of exercise. There is evidence that humans possess considerable respiratory, and hence, ventilatory reserve during strenuous physical activity, with this reserve estimated to be between 15% and 40% of a healthy person's maximum voluntary ventilation.
In the prior art, the control of respiration has been left to a passive, intrinsic, and involuntary system that operates through a number of reflex feedback mechanisms, with CO2 levels and pH being large determinants. However, the considerable respiratory reserve available in most instances indicates that there is physiological room for considerable voluntary manipulation of respiration.
By utilizing the considerable respiratory reserve presently unused, one can affect a net drop in CO2 despite rising lactic acid levels, that is, by increasing ventilation relatively early during exercise, to create a systemic alkalosis reserve. By these means, acidosis can be eliminated along with its concomitant detrimental effects.
A systemic alkalosis is preferred or at least a neutral systemic pH during exercise or performance as alkalosis itself is known to enhance performance. There is current evidence that performance is enhanced during the state of metabolic alkalosis. Instead of creating a systemic alkalosis via compensatory ventilatory changes, buffering is accomplished via metabolic means, that is, through ingestion of an alkaline drink such as sodium bicarbonate or calcium citrate. The effects of such treatment are, unfortunately, short lived and, contrary to its intent, may lead to a paradoxical increase in cellular acidosis. This effect is not surprising given the buffering equation of Table 3. With a net increase in bicarbonate (ingested) the equation in Table 3 is directed to the left leading to an increased production of free hydrogen ions (H+), and therefore, more acidosis. This paradoxical increase in acidosis is well known to those medical personnel performing emergency resuscitation using Advanced Cardiac Life Support (ACLS) guidelines. Bicarbonate is no longer recommended as routine treatment in cardiac arrest as it leads to the development of a paradoxical acidosis.
In addition, it has also been reported that intracellular pH is unaffected by ingesting HCO3− and that its benefits are obtained from the extracellular alkalosis alone. This has lead to the hypothesis that the cellular membrane is impermeable to HCO3− molecule.
Ventilation of CO2 is the single most effective way of decreasing intracellular and mitochondrial levels of CO2, with alveolar CO2 levels being nearly equivalent to that of the intracellular and mitochondrial CO2 levels, where ATP is generated. The greater the quantity of CO2 ventilated, the lesser the quantity of CO2 remaining in cells and mitochondria. This leads to a decrease in intra-cellular/intra-mitochondrial acidosis, or increase in alkalosis. In contrast to the ingestion of HCO3− and its resultant metabolic alkalosis, the mitochondrial pH can be altered via ventilation, specifically by maximizing CO2 ventilation.
Until recent times, difficulties in obtaining real-time measurement of blood CO2 levels precluded effective techniques in the management of respiration. Traditionally, arterial CO2 could only be measured after an invasive and complicated procedure such as the collection of an arterial blood sample by arterial puncture. Similarly complicated and inconvenient efforts are required to approximate blood CO2 levels after collection of expired (alveolar) CO2. The necessity for cumbersome or invasive equipment essentially precluded regular or routine measurement in an exercise setting. However, the availability of transcutaneous CO2 monitoring allows direct real-time monitoring of blood CO2 levels, during exercise, and can be used to assist in creating a feedback loop method of the instant invention that instructs the athlete in means to maximize both the efficiency of respiration and total amount of CO2 expired both before and during athletic performance.